1. Technical Field
The present invention relates to compounds having a basic bicyclic structure of a dihydroquinazolin compound and bearing D2 receptor antagonist and 5-HT1A receptor agonist properties, a method of making the compounds, and a method for treating schizophrenia by administering an effective dose of one or more of the compounds.
2. Description of the Related Art
The “background” description provided herein is for the purpose of generally presenting the context of the disclosure. Work of the presently named inventors, to the extent it is described in this background section, as well as aspects of the description which may not otherwise qualify as prior art at the time of filing, are neither expressly or impliedly admitted as prior art against the present invention.
Schizophrenia is a severe psychiatric illness afflicting 1% of the population worldwide. The diagnosis of the disease is based on diverse and variably expressed symptoms which can be grouped as positive and negative. The positive symptoms include disorganized thought, delusions and auditory hallucinations whereas the most characteristic negative symptoms are emotional flattening, poverty of speech and motivational deficits (Diagnostic and Statistical Manual of Mental Disorders. 4th ed., text revision, American Psychiatric Association, Washington, D.C., p. 297-343 (2000)—incorporated herein by reference in its entirety). FIG. 1 depicts the first-generation antipsychotics or typical antipsychotics such as chlorpromazine 1 and haloperidol 2. Both chlorpromazine 1 and haloperidol 2 are dopamine antagonists which alleviate positive symptoms including hallucinations, agitation and delusions but fail to control the negative symptoms such as blunted affect, emotional withdrawal and cognitive deficits. In addition these therapeutics develop extrapyramidal symptoms (EPS) and hyperprolactinemia, respectively (D. C. Goff, R. I. Shader. Non-neurological side-effects of antipsychotic drugs. In S. R. Hirsch, D. Weinberger, editors. Schizophrenia. 2nd ed., Blackwell Publishing, Oxford, p. 573-88 (2002)—incorporated herein by reference in its entirety) The ‘second-generation’ or atypical antipsychotics, such as clozapine 3, depicted in FIG. 1, combine D2 receptor antagonism with activity at other receptors, on the premise that a suitable balance of pharmacological activity should broaden the spectrum of therapeutic efficacy and reduce EPS. With respect to classical neuroleptics, clozapine shows significantly greater efficacy, including an improved effect on negative symptoms, and causes a marked increase in dopamine output in the prefrontal cortex (H. Y. Meltzer, Psychopharmacology, 99, S18 (1989)—incorporated herein by reference in its entirety) Clozapine, however, is associated with its own set of serious side effects including weight gain, diabetes and an increased risk of seizures and agranulocytosis (L. H. Lindstrom, Acta. Psychiatr. Scand., 77, 524 (1988)—incorporated herein by reference in its entirety)
Several preclinical observations suggest that combining 5-HT1A and D2 receptor properties may provide a mutually complementary balance of pharmacological activity with reduced undesirable responses (E. P. Prinssen, F. C. Colpaert, W. Koek, Eur. J. Pharmacol., 453, 217 (2002)—incorporated herein by reference in its entirety) Indeed, numerous mechanistic considerations (A. Newman-Tancredi, M. B. Assie, N. Leduc, A. M. Ormiere, N. Danty, C. Cosi, Int. J. Neuropsychopharmacol., 8, 341 (2005); M. B. Assie, V. Ravailhe, V. Faucillon, A. Newman-Tancredi, J. Pharmacol. Exp. Ther., 315, 265 (2005); L. A. B. Slot, L. D. Vries, A. Newman-Tancredi, D. Cussac, Eur. J. Pharmacol., 534, 63 (2006)—each incorporated herein by reference in its entirety) and preclinical evidence (L. A. B. Slot, M. S. Kleven, Neuropharmacology, 49, 996 (2005); M. S. Kleven, C. Barret-Grevoz, L. A. B. Slot, A. Newman-Tancredi, Neuropharmacology, 49, 135 (2005); R. A. Bantick, J. F. W. Deakin, P. M. Grasby, J. Psychopharmacol., 15, 37 (2001)—each incorporated herein by reference in its entirety) support the potential of such a combination. As a result, adoprazine 4 (SLV-313) and bifeprunox 5, bearing potent D2 receptor antagonist and 5-HT1A receptor agonist properties, were developed as depicted in FIG. 1 (A. C. McCreary, J. C. Glennon, C. R. Ashby Jr, H. Y. Meltzer, Z. Li, J-H. Reinders, M. B. Hesselink, S. K. Long, A. H. Herremans, H. van Stuivenberg, R. W. Feenstra, C. G. Kruse, Neuropsychopharmacology, 32, 78 (2007)—incorporated herein by reference in its entirety)
The failure of 4 and 5 to oppose phencyclidine-induced social interaction deficits demonstrates the difficulty of balancing activity at these sites (A. Newman-Tancredi, Curr. Opin. Invest. Drugs, 11, 802 (2010)—incorporated herein by reference in its entirety) Compounds having effective ratios of D2 and 5-HT1A activities are described herein (S. Cuisiat, N. Bourdiol, V. Lacharme, A. Newman-Tancredi, F. Colpaert, B. Vacher, J. Med. Chem., 50, 865 (2007)—incorporated herein by reference in its entirety)